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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the subject of the invention is derivatives of 7 / - / - indazole-3-carboxamides, their preparation and their use in therapy.
• US Patent 3,457,269 describes. / - / - indazoIe-3-carboxamides useful as hypotensive agents.
• cyclin dependent kinase inhibitors such as cdkl, cdk2 and cdk4.
• the invention meets this aim by proposing derivatives of 7 / - / - indazole-3-carboxamides, which have inhibition effects on cdkl, cdk2 and cdk4.
• the first object of the invention is compounds corresponding to the general formula (I):
• Ri represents a hydrogen atom, a halogen atom, an NH 2 , NHR 2 , NHCOR 2 , NO 2 , CN, CH 2 NH 2 ,
• Ri represents a phenyl optionally substituted by one or two substituents chosen from a halogen atom, a hydroxy, C ⁇ - 6 alkyl, Ci, 6 alkoxy, NH 2 , NHR 2 , NR 2 R 3 ; or R ⁇ represents a heteroaromatic group optionally substituted by one or two substituents chosen from a halogen atom, a hydroxy, a heteroaromatic group, C ⁇ - 6 alkyl, NH 2) NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 , CH2XR 2 where X represents an atom chosen from O, NH and S; Ar represents a phenyl group optionally substituted by one or two substituents chosen from a halogen atom, a C1-6 alkyl, Ci _ 6 thioalkyl, C ⁇ - 6 alkoxy, CH 2 OH, phenoxy, morpholinyl, -CH 2
• R 2 and R 3 independently of one another represent a C ⁇ - 6 alkyl optionally substituted by a CONH group 2) by a phenyl or by a heteroaromatic group; or R and R 3 represent, independently of one another, a phenyl or a heteroaromatic group; n represents 0, 1, 2 or 3.
• a first family of preferred compounds consists of the compounds for which: Ri represents a hydrogen or halogen atom, NH 2) NHR 2 , NHCOR 2) N0 2 , CN, CH 2 NH 2j CH 2 NHR 2 ; or Ri represents a phenyl optionally substituted with one or two substituents chosen from a halogen atom, a hydroxy, C ⁇ - 4 alkyl, C ⁇ - 6 alkoxy, NH 2) NHR 2 , NR2R3; or else Ri represents a heteroaromatic group optionally substituted by one or two substituents chosen from a halogen atom, a hydroxy, a heteroaromatic group, a C ⁇ - 6 alkyl, an NH 2 , NHR 2 , NHCOR 2> COOR 2 , CONH2, CONHR2, CH 2 XR 2 where X represents an atom chosen from O, NH and S; and / or Ar represents a phenyl group optionally substitute
• R 2 and R 3 represent, independently of one another, a C ⁇ - 6 alkyl optionally substituted by a CONH 2 group, by a phenyl or by a heteroaromatic group; or R 2 and R 3 represent, independently of one another, a phenyl or a heteroaromatic group; and / or n represents 0, 1, 2 or 3; with the condition that
• a second family of preferred compounds consists of the compounds for which:
• Ar represents a phenyl group substituted by one or two substituents chosen from a bromine or iodine atom, a C 2 -6 alkyl, C 2 - 6 thioalkyl, C 2 -6 alkoxy, CH 2 OH, phenoxy, morpholinyl, -CH 2 -morpholinyl, NH 2 , NHR 2 , NR 2 R 3 , NHS0 2 R 2 , CN, S0 2 R 2 , S0 2 NH 2 , S0 2 NHR 2 , COOH , COOR 2 , CONH 2) CONHNH 2 , CONHR 2 , CH 2 NHR 2 , CH 2 NR 2 R 3 ; or Ar represents a heteroaromatic group chosen from a pyrrolyl, imidazolyle, pyrazolyle, triazolyle, tetrazolyle, thiazolyle, isothiazolyle, 1, 3,4-thiadiazol
• R 2 and R 3 independently of one another represent a Ci. 6 alkyl optionally substituted with a CONH 2 group, with a phenyl or with a heteroaromatic group; or R 2 and R 3 represent, independently of one another, a phenyl or a heteroaromatic group; and / or n represents 0, 1, 2 or 3;
• Ri represents a halogen atom, NH 2 , NHR 2 , NHCOR 2 , N0 2 , CN, CH 2 NH 2 , CH 2 NHR 2 ; or Ri represents a phenyl optionally substituted by one or two substituents chosen from a halogen atom, a hydroxy, C 1 - 6 alkyl, C ⁇ - ⁇ alkoxy, NH 2 , NHR 2 , NR 2 R 3 ; or Ri represents a heteroaromatic group-optionally substituted by one or two substituents chosen from a halogen atom, a hydroxy, a heteroaromatic group, a C ⁇ - 6 alkyl, an NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 , CH 2 XR 2 where X represents an atom chosen from O, NH and S; then Ar represents a phenyl group optionally substituted by one or two substituents chosen from a bromine,
• a third family of preferred compounds consists of the compounds for which:
• Ar represents a phenyl substituted by one or two substituents chosen from a bromine atom, a CH 2 OH, phenoxy, NH 2 , NHR 2 , NR 2 R 3 , CN, SO 2 NH 2 , COOH, COOR 2 , CONH 2 ; or Ar represents a heteroaromatic group chosen from an imidazolyl, 1,3,4-thiadiazolyl, pyrazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, optionally substituted with one or two substituents; or Ar represents a pyridinyl substituted with one or two substituents; the substituents being chosen from a halogen atom, more particularly a chlorine, a COOH, a Ci. 6 alkyl, more particularly methyl, C ⁇ - 6 alkoxy, more particularly methoxy; and or
• R 2 and R 3 independently of one another represent a C - 6 alkyl, more particularly a methyl or an ethyl; or R 2 and R 3 represent, independently of one another, phenyl; and / or n represents 0, 2 or 3; - when Ri represents a halogen atom, more particularly a bromine or an iodine, an NH 2 , NHCOR 2 , NO 2) CN, CH 2 NH 2 ; or R 1 represents a phenyl; or Ri represents a heteroaromatic group, more particularly a pyrazolyle, tetrazolyle, thiazolyle, oxazolyle, pyridinyle, pyrimidinyle, quinolinyle, isoquinolinyle, pyrrolo [2,3-c] pyridinyle, optionally substituted by one or two substituents chosen among an atom of halogen, more particularly chlorine or fluorine, hydroxy, heteroaromatic group, more particularly
• R 2 and R 3 independently of one another represent a C 1 - 6 alkyl, more particularly a methyl, ethyl or 2-methylpropyl, optionally substituted by a CONH 2 group or by a phenyl; or R 2 and R 3 represent, independently of one another, a phenyl or a heteroaromatic group, more particularly a pyridinyl or pyrimidinyl; and / or n represents 0 or 1.
• a fourth family of particularly preferred compounds consists of the compounds for which: Ri represents a heteroaromatic group optionally substituted by one or two substituents chosen from a halogen atom, a hydroxy, a heteroaromatic group , C ⁇ - 6 alkyl, NH 2 , NHR 2 , NHCOR, COOR, CONH 2 , CONHR 2 , CH 2 XR 2 where X represents an atom chosen from O, NH and S; and / or Ar represents a phenyl group optionally substituted by one or two substituents chosen from a halogen atom, a C1-6 alkyl, C ⁇ - ⁇ thioalkyl, Ci- ⁇ alkoxy, CH 2 OH, phenoxy, morpholinyl, -CH 2 -morpholinyl, NH 2 , NHR 2 , NR 2 R 3 , NHSO2R2, CN- SO2R2, S0 2 NH 2 , - S0 2
• a fifth family of particularly preferred compounds consists of the compounds for which: Ri represents a heteroaromatic group, more particularly a pyrazolyle, thiazolyle, oxazolyle, pyridinyle, isoquinolinyle, pyrrolo [2,3-c ] pyridinyl, optionally substituted with one or two selected substituents.
• a halogen atom more particularly a chlorine, a heteroaromatic group, more particularly a pyridinyl, a C 1 - 6 alkyl, more particularly a methyl, an NH 2 , CONHR 2 ; and / or Ar represents a phenyl optionally substituted by one or two substituents chosen from morpholinyl, -CH 2 -morpholinyl, NHS0 2 R 2 , CN, S0 2 R 2 , S0 2 NH 2 , S0 2 NHR 2 , COOH, CH 2 NHR 2 , CH 2 NR 2 R 3 ; or Ar represents a heteroaromatic group, more particularly a pyridinyl, optionally substituted by a C 1 - 6 alkoxy, preferably a methoxy; and or
• R 2 and R 3 represent, independently of one another, a C ⁇ - 6 alkyl, more particularly methyl or ethyl, optionally substituted by a CONH 2 group or by a phenyl; or R 2 and R 3 represent, independently of one another, a heteroaromatic group, more particularly a pyridinyl or pyrimidinyl; and / or n represents 0 or 1.
• a subject of the invention is also, among the compounds of general formula (I), compounds corresponding to the general formula (I '):
• Ri represents a hydrogen, halogen atom, NH 2 , NHR 2 , NHCOR 2 , N0 2 , CN, CH 2 NH 2 ,
• Ri represents a phenyl optionally substituted with one or two substituents chosen from a halogen atom, a hydroxy, C 1 -6 alkyl, C ⁇ - 6 alkoxy, NH 2 , NHR 2 , NR 2 R 3 ; or Ri represents a heteroaromatic optionally substituted by one or more substituents chosen from a heteroaromatic, C ⁇ . 6 alkyl, NH 2 , NHR 2 , NHCOR 2 , CONH2, CONHR2, CH2XR2 where X represents an atom chosen from 0, NH and S;
• Ar represents a phenyl group optionally substituted by one or two substituents chosen from a halogen atom, a C1.6 alkyl, C ⁇ - 6 thioalkyle, C ⁇ - 6 alkoxy,
• Ar represents a heteroaromatic, optionally substituted by one or two substituents chosen from a halogen atom, a COOH, C ⁇ - 6 alkyl,
• R 2 and R 3 independently of one another represent a C ⁇ - 6 alkyl optionally substituted by a phenyl or a heteroaromatic; or R 2 and R 3 independently represent one of - Hautre a phenyl or a heteroaromatic; n represents 0, 1, 2 or 3.
• a first family of preferred compounds consists of the compounds for which: Ri represents a hydrogen, halogen atom, NH 2 , NHR 2 , NHCOR 2 , N0 2 , CN , CH 2 NH 2 , CH 2 NHR 2 ; or Ri represents a phenyl optionally substituted by one or two substituents chosen from a halogen atom, a hydroxy, C alkyl, C ⁇ - 6 alkoxy, NH 2 , NHR 2 , NR 2 R 3 ; or Ri represents a heteroaromatic optionally substituted by one or more substituents chosen from a heteroaromatic, C ⁇ - 6 alkyl, NH 2 , NHR 2 ( NHCOR 2 , CONH 2 , CONHR 2 , CH 2 XR 2 where X represents an atom chosen from O, NH and S; and / or Ar represents a phenyl optionally substituted by one or two substituents chosen from a
• Ar represents a heteroaromatic, optionally substituted by one or two substituents chosen from one halogen atom, COOH, Ci. 6 alkyl, d - 6 alkoxy; and / or
• R 2 and R 3 represent, independently of one another, a C ⁇ - 6 alkyl optionally substituted by a phenyl or a heteroaromatic or R 2 represents a phenyl or a heteroaromatic; and / or n represents 0, 1, 2 or 3; with the condition that
• R 1 represents a hydrogen atom if n represents 0 and Ar is a phenyl, then the phenyl is necessarily substituted as defined above, the methyl, methoxy, thiomethyl substituents, chlorine atom being excluded; if n represents 1, then and Ar is a phenyl, then the phenyl is necessarily substituted as defined above, the methyl and chlorine atom substituents being excluded; if n represents 1, then and Ar is a pyridinyl, then the pyridinyl is necessarily substituted as defined above; if n represents 2 and Ar is phenyl, then the phenyl is necessarily substituted as defined above, the methoxy substituent being excluded; if n represents 3 and Ar is a pyridinyl, then the pyridinyl is necessarily substituted as defined above;
• a second family of preferred compounds consists of the compounds for which:
• Ar - represents a phenyl substituted by one or two substituents chosen from a bromine or iodine atom, a C 2 . 6 alkyl, C 2 -6 thioalkyl, C 2 .
• Ar represents a chosen heteroaromatic among a pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, 1, 3,4-thiadiazolyl, pyridazinyl, pirimidinyl, pyrazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, optionally substituted by one or two substituents; or Ar represents a pyridinyl substituted by one or two substituents; the substituents being selected from halogen, COOH, C
• Ri represents a halogen atom, NH 2 , NHR 2 , NHCOR 2 , N0 2 , CN, CH 2 NH 2 , CH 2 NHR 2 ; or R 1 represents a phenyl optionally substituted by one or two substituents chosen from a halogen atom, a HYDROXY, Ci.
• Ri represents a heteroaromatic optionally substituted by one or more substituents chosen from a heteroaromatic, C 6 alkyl, NH 2 , NHR 2 , NHCOR 2 , CONH 2 , CONHR 2 , CH 2 XR 2 where X represents an atom chosen from O , NH and S; then Ar represents a phenyl optionally substituted with one or two substituents chosen from a bromine or iodine atom, a C 2 - ⁇ alkyl, C 2 - ⁇ thioalkyl, C 1 -6 alkoxy, CH 2 OH, phenoxy, NH 2 , NHR 2 , NR 2 R 3 , CN, S0 2 NH 2 , S0 2 NHR 2 , COOH, COOR 2 , CONH 2 , CONHR 2 ; or Ar represents a heteroaromatic, optionally
• R 2 and R 3 independently of one another represent a C ⁇ - 6 alkyl optionally substituted by a phenyl or a heteroaromatic; or R 2 and R 3 represent, independently of one another, a phenyl or a heteroaromatic; and / or n represents 0, 1, 2 or 3.
• t and z can take the values from 1 to 6, a carbon chain being able to have from t to z carbon atoms, for example Ci. 6 a carbon chain which may have from 1 to 6 carbon atoms;
• a C ⁇ - 6 alkyl group represents a carbon chain of 1 to 6 carbon atoms, linear or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl ...
• - thioalkyle a group -S-alkyl with saturated, linear or branched aliphatic chain; - halogen atom, fluorine, chlorine, bromine or iodine;
• heteroaromatic group a cyclic aromatic group comprising between 5 and 9 carbon atoms and comprising between 1 and 4 heteroatoms, such as nitrogen, oxygen or sulfur.
• heteroaromatic groups mention may be made of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1, 3,4-thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, piriminyl groups 1, 3,5-triazinyl, indolyle, isoindolyle, indazolyle, benzimidazolyle, benzothiazolyle, quinolinyle, isoquinolinyle, pyrrolo [2,3-c] pyridinyle.
• the compounds of general formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
• the compounds of general formula (I) can exist in the form of tautomers.
• the subject of the invention is the compounds of the invention in all their tautomeric forms.
• the compounds of general formula (I) can exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids useful, for example, for the purification or isolation of the compounds of general formula (I) also form part of the invention.
• the compounds of general formula (I) can be in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
• the present invention also relates to processes for the preparation of the compounds of general formula (I).
• the compounds of the invention can be prepared by the methods illustrated in the diagrams which follow, the operating conditions of which are conventional for a person skilled in the art.
• protective group PG means a group which makes it possible to prevent the reactivity of a function or position, during a chemical reaction which may affect it, and which restores the molecule after cleavage according to methods known to those skilled in the art. . Examples of protecting groups as well as methods of protection and deprotection are given, among others, in Protectiv ⁇ groups in Organic Synthesis, Green et al., 2 nd Ed. (John Wiley & Sons, Inc., New York).
• R 1 represents a halogen atom, an NO 2 or a CN
• the compounds of general formula (I) can be prepared by the method illustrated in scheme 1.
• This method consists in transforming an indole of general formula (II), where Ri is an NO 2 , a CN or a halogen atom, into indazole-3-carbaldehyde of general formula (III) for example with nitrous acid .
• the compound of general formula (III) is then protected in basic medium by a PG group, of trimethylsilylethoxymethyl (SEM) or mesitylenesulfonyl (Mts) group to give the indazole-3-carbaldehyde protected in position 1 of general formula (IV).
• SEM trimethylsilylethoxymethyl
• Mts mesitylenesulfonyl
• the compound (IV) is oxidized to indazole-3-carboxylic acid of general formula (V), for example by reaction with sodium chlorite.
• Obtaining the indazole-3-carboxamide protected in position 1 of general formula (VII) is done by coupling the compound of general formula (V) with an amine of general formula Ar (CH 2 ) nNH 2 (VI) in which Ar and n are as defined in the general formula (I).
• This coupling reaction can be carried out by activation of a compound of general formula (V) by coupling reagents, such as carbonyldiimidazole or isopropyl or isobutyl chloroformate.
• the deprotection of the compound of general formula (VII) can be done either by the action of a base such as sodium hydroxide r is in the presence of tetrabutylammonium fluoride (TBAF) and ethylenediamine, or even in the presence of trifluoroacetic acid then heating with ethylenediamine.
• TBAF tetrabutylammonium fluoride
• This deprotection step makes it possible to obtain indazole-3-carboxamide of general formula
• the compounds of general formula (I), where R represents NH 2 are obtained by reduction of a compound of general formula (I), where Ri is an NO 2 , as obtained according to scheme 1, for example in presence of tin chloride.
• NHCOR 2 are obtained by functionalization of the corresponding compounds of general formula (I), where Ri is NH 2 , according to techniques known to those skilled in the art.
• the compounds of general formula (I) where Ri represents a CH 2 NH 2 are obtained by hydrogenation at atmospheric pressure of a compound of general formula (I), where Ri is a CN, as obtained according to scheme 1, for example in the presence of palladium on carbon.
• the compounds of general formula (I) can be obtained according to one of the methods illustrated in schemes 1, 2 and 3. However, when Ri represents an oxazolyl group, the compounds of formula (I) can be obtained according to scheme 4 and when R 1 represents a thiazolyl group, the compounds of formula (I) can be obtained according to scheme 5.
• Scheme 2 illustrates an alternative method of preparing the compound of general formula (VII) from 5-iodoindole.
• the compound of general formula (IVa), where SEM is a trimethylsilylethoxymethyl group is obtained by repeating the first two steps illustrated in scheme 1.
• a Suzuki reaction carried out for example in presence of a boronic acid of general formula R 1 B (OH) 2 (VIII), in which Ri represents an optionally substituted phenyl or heteroaromatic group as defined in general formula (I), of an inorganic base, such as sodium carbonate (Na 2 C0 3 ), and palladium (0), makes it possible to obtain the compound of general formula (IV), in which PG represents a SEM group.
• the compound of general formula (I), where Ri represents an optionally substituted phenyl or heteroaromatic group as defined in general formula (I) is obtained from the compound of general formula (IV) by repeating the last three steps illustrated in figure 1.
• Scheme 3 illustrates a method of preparation from 5-iodo- or 5-bromoisatin.
• 5-iodo- or 5-bromoindazolecarboxylic acid can be obtained by opening the indoledione cycle of 5-iodo- or 5-bromoisatin, for example in the presence of sodium hydroxide, then by diazotization, for example by means of nitrous acid, and finally by reduction and formation of the indazole cycle, for example in the presence of tin chloride (SnCI 2 ).
• the 5-iodo- or 5-bromoindazole-3-carboxylic acid obtained is then protected in basic medium, for example by an SEM group, to give the compound of general formula (IX), in which X represents a bromine atom or diode.
• IndazoIe-3-carboxamide of general formula (X) can be obtained by coupling the compound of general formula (IX) with an amine of general formula Ar (CH 2 ) nNH 2 (VI), in which Ar and n are such as defined in the general formula (I).
• This coupling reaction can be carried out by activation of a compound of general formula (IX) by coupling reagents, such as carbonyidiimidazole or isopropyl or isobutyl chloroformate.
• Scheme 4 illustrates a method for preparing the compounds of general formula (VIIa), that is to say the compounds of general formula (VII) for which R 1 represents an oxazolyl group and PG represents a SEM group.
• the compound of general formula (X), as defined above and in which X represents an iodine atom, is formylated for example in the presence of carbon monoxide and a palladium complex, such as tetrakis (triphenylphosphine ) palladium, then a reducing agent, such as tributyltin hydride in a solvent, such as tetrahydrofuran (THF).
• a palladium complex such as tetrakis (triphenylphosphine ) palladium
• a reducing agent such as tributyltin hydride in a solvent, such as tetrahydrofuran (THF).
• the compound of general formula (XIII) thus obtained is heated to reflux in a solvent, such as methanol, in the presence of tosylmethylisocyanate (TosMIC) and of a base such as potassium carbonate (K 2 C0 3 ), to obtain the compound of general formula (VIIa).
• a solvent such as methanol
• TosMIC tosylmethylisocyanate
• K 2 C0 3 potassium carbonate
• Scheme 5 illustrates a method of preparing the compounds of general formula (Vllb), that is to say the compounds of general formula (VII) for which R 1 represents a thiazolyl group and PG represents a SEM group.
• the thiazolyl group is introduced by heating the compound of general formula (X), as defined above and in which X represents an iodine atom, in the presence of the derivative of formula (XIV) illustrated in scheme 5, of tetrakis (triphenylphosphine) palladium in anhydrous THF then by acidification.
• the derivative of formula (XIV) is prepared from 2-trimethylsilyl (thiazole), in the presence of a strong base, such as butyllithium, by reaction of zinc chloride (ZnCI 2 ) in solution in anhydrous ether .
• the compound of general formula (Vllb) thus obtained is deprotected according to the last step of scheme 1 in order to obtain the compound of general formula (I), where R 1 represents a thiazolyl group.
• the compounds of general formula (V), (VII) and (X) are new and also form part of the invention. They are useful as synthesis intermediates for the preparation of the compounds of general formula (I).
• the percentage in parentheses represents the UV purity of the compound.
• Indazole-3-carboxylic acid (810 mg, 5 mmol) is heated to 60 ° C. in the presence of carbonyidiimidazole (891 mg, 5.5 mmol) in N, N-dimethylformamide (DMF) (14 ml) under argon for 3 h.
• 1- (3-aminopropyl) imidazole (597 ⁇ l, 5 mmol) dissolved in DMF (2 ml) is added and the mixture is heated for 2 h and 20 min at 60 ° C. After cooling, the DMF is evaporated under vacuum to give a yellow oil which is chromatographed on 54 g of silica. The compound obtained is eluted with an ethyl acetate (AcOEt) / methanol (MeOH) (9/1) mixture. 690 mg of product are obtained. Mp: 154-155 ° C
• This compound is synthesized in a similar manner to the procedure described in Example 2 by coupling indazole-3-carboxylic acid and N-phenyl-1,4-phenylenediamine on the Jjrimol scale, but using dicyclohexyl - carbodiimide (DCC) as a coupling reagent.
• DCC dicyclohexyl - carbodiimide
• This compound is synthesized in a similar manner to the procedure described in Example 5. The synthesis is carried out on a scale of 5 mmol. The final compound is recrystallized from AcOEt.
• 5-iodoisatin (5 g, 18.3 mmol) is heated in the presence of sodium hydroxide (0.77 g, 19.2 mmol in 12 ml H 2 0) until dissolution then the reaction mixture is cooled to 0 ° vs.
• a solution of sodium nitrite previously cooled to 0 ° C (1.26 g, 18.3 mmol in 5.5 ml H 2 0) is added.
• the paste obtained is added in small portions, with vigorous stirring, to a solution of sulfuric acid (3.40 g, 34.8 mmol in 37 ml H 2 0) pre-cooled to 0 ° C so that the temperature does not not exceed 4 ° C.
• the reactor is degassed several times with argon and then, under argon, tetrakis (triphenylphosphine) palladium (48 mg, 0.03 equiv.) Is added.
• the reaction mixture is heated to 85 ° C overnight.
• the solvents are evaporated in vacuo and the residue is extracted with AcOEt / H 2 0.
• the organic phase is dried and evaporated.
• the crude product is chromatographed on silica gel (200 g). Elution with AcOEt / MeOH (95/5) provides, after evaporation, 370 mg of product.
• reaction mixture is acidified with 4N HCl (1.2 ml), concentrated under vacuum and then diluted with H 2 O.
• the precipitate is filtered, washed with CH 3 OH and diethyl ether.
• the solid obtained is recrystallized from CH 2 CI 2 / MeOH.
• This compound is synthesized in a manner analogous to intermediate 10.4, by a Suzuki reaction between intermediate 10.3 and intermediate 11.2, on a scale of 1.29 mmol. It is recrystallized from a CHCI 3 / AcOEt mixture.
• This compound is synthesized in a manner analogous to intermediate 10.4, by a Suzuki reaction between intermediates 10.3 and 12.3, on the scale of 1.37 mmol. It is chromatographed on silica gel, eluting with AcOEt.
• reaction mixture is heated using an oil bath controlled at 85 ° C for 5 h and then concentrated in vacuo.
• the residue is taken up in AcOEt.
• the organic solution is washed with brine, dried and then evaporated to give a crude product which is purified on silica gel (150 g). Elution in a gradient from CH 2 CI 2 to CH 2 CI 2 / AcOEt (9/1) provides 0.84 g of product.
• This compound is prepared similarly to intermediate 13.5 by coupling intermediate 13.4 to ethyl 4-aminobenzoate, on a 2.4 mmol scale.
• the crude compound is purified on silica gel (80 g).
• This compound is prepared by cutting the mesitylenesulfonyl protecting group from intermediate 16.1 with sodium hydroxide in a manner analogous to the procedure described in Example 15.
• the mesitylenesulfonyl protecting group of intermediate 15.4 is cut with sodium hydroxide, in a manner analogous to Example 15, on the scale of 0.7 mmol. 0.20 g of product are obtained in the form of a yellow solid.
• N- (pyridin-4-yl) -5-aminomethyl-1 H-indazole-3-carboxamide methanesulfonic acid salt A solution of the compound obtained in Example 19 (263 mg, 1 mmol) in an AcOH / H 2 0 (25 ml / 5 ml) is hydrogenated at atmospheric pressure in the presence of 10% Pd / C (50 mg) for 3 h. The catalyst is filtered and the mixture is concentrated in vacuo. The residue is crystallized from an isopropanol / H 2 0 mixture. 128 mg of product are obtained.
• the residue is purified on silica gel, eluting along a gradient from AcOEt / petroleum ether (1/9) to AcOEt / petroleum ether (1/4).
• the purified compound is recrystallized from AcOEt / petroleum ether. 3.60 g of product are obtained in the form of a brown solid.
• the DMF is evaporated.
• the residue is taken up in AcOEt / H 2 0.
• the organic phase is washed with 1N HCl.
• the aqueous phase is combined and brought to basic pH by the addition of 1N sodium hydroxide and then extracted with AcOEt.
• the organic phase is dried over MgSO 4 and then evaporated.
• 504 mg of product are obtained in the form of a powder.
• the compound is obtained in a similar manner to the procedure described in Example 11 by cutting the protective group SEM of intermediate 22.3 (500 mg, 0.86 mmol).
• the crude product is taken up in MeOH.
• the compound obtained is isolated by filtration.
• Intermediary 23.3 and intermediary 10.3 are coupled under conditions of
• the compound is obtained in a similar manner to the procedure described in Example 11 by cutting the protective group SEM of intermediate 23.4 (380 mg, 0.59 mmol). The crude product is washed with THF and then with diethyl ether.
• 150 mg of product are obtained in the form of a yellowish powder.
• sodium cyanoborohydride NaBH 3 CN, 3.3 g, 50 mmol
• Stirring is continued for 2 h at room temperature.
• the reaction mixture is diluted with AcOEt (600 ml) then is washed with water.
• the organic phase is dried over Na 2 S0 and then evaporated.
• the residue is purified on silica gel, eluting with an AcOEt / petroleum ether mixture (1/4).
• This compound is prepared from intermediate 26.2, analogously to intermediate 23.3, on a scale of 1.6 mmol.
• the crude product is purified on silica gel, eluting with an AcOEt / methylene chloride mixture (1/5). 470 mg of product are obtained.
• Bromine (5.07 g, 31.7 mmol) is added dropwise to a suspension of intermediate 29.1 (4.04 g, 28.4 mmol) in H 2 O (40 ml).
• the mixture is heated with an oil bath at a temperature of 90 ° C for 1 h. After cooling, the mixture is filtered. The solid is washed with H 2 0 and then dried in a desiccator in the presence of silica gel.
• This compound is obtained by reduction of 3-bromo-4-methyl-5-nitropyridine (intermediate 29.5) with iron in a manner analogous to the synthesis of intermediate 29.7, on the scale of 10 mmol. 1.20 g of product are obtained in the form of a cream-colored solid.
• This compound is obtained in a similar manner to Example 11 by cutting the SEM protective groups from intermediate 31.2 (550 mg, 0.97 mmol) with TFA followed by heating in the presence of ethylenediamine. The reaction mixture is filtered. The solid is stirred in the presence of CHCI 3 / H 2 O. The fraction insoluble is stirred in the presence of MeOH for 1 h and then filtered to give the expected product.
• a stream of carbon monoxide is introduced for 15 min into a solution of intermediate 9.3 (4.95 g, 10 mmol) in THF (50 ml). Tetrakis (triphenylphosphine) palladium (578 mg, 0.5 mmol) is added and then a stream of carbon monoxide is introduced for 10 min.
• the mixture is brought to 50 ° C. and a solution of tributyltin hydride (3.05 ml, 11 mmol) in THF (20 ml) is added slowly over 2 h 30 min. After cooling, water (0.5 ml) is added and the reaction mixture is evaporated. The residue is purified on silica gel, eluting with MeOH / AcOEt / CH 2 CI (2/29/69). 2.65 g of product are obtained in the form of a yellow solid.
• the compounds of the invention have been the subject of pharmacological tests which have shown their interest as active substances in therapy. They have in particular been tested for their inhibitory effects on certain cyclin dependent kinases (cdks) such as cdkl (also called cdc2), cdk2 and cdk4.
• cdks cyclin dependent kinases
• Cdks are protein kinases (serine / threonine) which play a decisive role in the progression of the cell cycle, functioning only by being associated with cyclins. Within these associations, the cyclins have a control function, while the function of the cdks is catalytic. To date, nine cdks (cdkl to cdk9) and eleven cyclins have been identified in humans.
• the individual cdks play distinct roles in the progression of the cell cycle and can be classified according to the stage of the cell cycle during which they intervene: G1 S transition (cdk2 / cyclin E, cdk4 / cyclin D1-D3, cdk6 / cyclin D1 , _çdk8 / cyclin C), phase .. S (cdk2 / cyclin A), G2 (cdc2 / cyclin A), G2 / M transition (cdc2 / cyclin B, cdk7 / cyclin H).
• the active cdk4 / cyclin D and cdk ⁇ / cyclin D phosphorylate the retinoblastoma protein pRb leading to its dissociation from the complex transcription factor complex E2F / DP1 and thus deactivating its transcription suppressor activity.
• the release of E2F / DP1 results in the activation of the transcription of a group of genes necessary for entry into the S phase, including thymidylate synthetase, dihydrofolate reductase and cyclin E.
• cyclin E stimulates cdk2 which acts by continuing the phosphorylation process of pRb, resulting in an irreversible commitment in a process of cell division and transition in phase S.
• cyclin A replaces cyclin E by activating cdk2, this resulting in a change in the specificity of the substrate for cdk2.
• E2F / DP1 is phosphorylated, which inactivates its transcription promoter activity. This results in a decrease in the synthesis of cyclin E and a transition to G2.
• the activity of cdk is inhibited by endogenous cdk inhibitors (cdkl: p15, p16, p18, p19, p21, p27 and p57).
• p16 a cdk4 and cdk6 inhibitor
• p27 another inhibitor, and the cyclin E or cyclin D co-activators are respectively either "over-expressed” or "under-expressed", in particular in breast, colon and non-small cell lung cancers , stomach, prostate, bladder, non-Hodgkin's lymphoma, ovaries. It has been shown that their altered expression is to be correlated with an increase in cdk2 and cdk4 activities.
• the compounds of the invention represent a new class of cdk inhibitors, the properties of which include the suspension of the cell cycle, the blocking of cell proliferation and apoptosis.
• the inhibitory activity on cdk2 was demonstrated in a test where the enzymatic activity cdk2 / Cyclin A is measured by quantification of 3 P from 33 P-ATP which was incorporated into the histone type III-S of thymus of veal (Sigma Ref: H-5505).
• the test is carried out in 50 mM HEPES medium, pH 7.2, in the presence of 1mM DTT (added temporarily), 1 mM MgCl 2 , 1 mM EGTA and 0.02% Tween 20 ..
• the concentration of histone is 0.4 mg / ml and the concentration of cold ATP is 10 ⁇ M.
• the concentration of 33 P-ATP is adjusted to an activity of approximately 300,000 cpm.
• the 5 ⁇ l inhibitor is added in solution in 10% aqueous DMSO, in order to have a final concentration of 1% in DMSO.
• the reaction mixture is incubated for 1 hour at room temperature.
• the reaction is stopped by depositing on a filter (Whatman P81, ion-exchange chromatography paper).
• the filters are washed twice by soaking for 20 min in a 37.5 mM phosphoric acid solution.
• the filters are placed in scintillation vials and the scintillant (aquasafe, Zinsser Analytic, 5ml) is added. These vials are then counted for 1 min on a Wallac counter.
• the most active compounds of the invention have an IC 50 (concentration inhibiting 50% of the enzymatic activity) of less than 20 ⁇ M.
• the inhibitory activity on cdkl has been demonstrated in a cdkl / Cyclin B test.
• the inhibitory activity of the compounds of the invention on cdkl is measured using the same protocol as for the cdk2 / Cycline A test. with the following modifications: the MgCl 2 concentration is 10 mmol and the ATP concentration is 0.1 ⁇ M.
• the most active compounds of the invention exhibit IC 5 o (concentration inhibiting 50% of enzyme activity) of less than 20 .mu.M.
• the inhibitory activity on cdk4 was demonstrated in a cdk4 / Cyc! Ine D1 test.
• the measurement of the inhibitory activity of the compounds of the invention on cdk4 is carried out according to the same protocol as for the cdkl / Cyclin B test.
• the substrate which can be the retinoblastoma protein at a concentration of 0.02 mg / ml or the peptide K10K (KAPLSPKKAK-NH 2 ) at a concentration of 1 mM.
• the most active compounds of the invention have an IC 50 (concentration inhibiting 50% of the enzymatic activity) of less than 20 ⁇ M.
• the compounds of the invention can be used in the treatment of pathologies in which an inhibitor of cdkl, cdk2, cdk4 provides a therapeutic benefit.
• pathologies are cancers, autoimmune and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, viral and fungal infections, degenerative diseases of the musculoskeletal system, hematological diseases, kidney diseases and liver disease caused by toxins or alcohol.
• the compounds of the invention have demonstrated in particular a potent antiproliferative activity on certain tumor cell lines.
• the inhibitors of the invention may behave like reversible cytostatic agents, which may be useful in treating the process of diseases with characteristic abnormal cell proliferation.
• the compounds of general formula (I) are also capable of modulating apoptosis, a process of physiological cell death, crucial for normal development and hemostasis. Alterations in apoptosis contribute to the pathogenesis of a multiplicity of human diseases.
• the compounds of general formula (I), as a modulator of apoptosis, can be useful for the treatment of human diseases exhibiting aberrations of apoptosis.
• the cdk inhibitors of the invention may be useful in the treatment of viral and fungal diseases, since the cdk are activated by viral cyclin (v-cyclin) and therefore are involved in viral replication and proliferation of viruses like the herpes virus and HIV-1.
• - cancers including but not limited to carcinoma, including cancer of the bladder, breast, colon, kidney, liver, lung, ovaries, pancreas, stomach, cervix uterus, thyroid, la-.pr-os.ate and skin; hematopoietic tumors of the lymphoid family, including acute lymphocytic leukemia, follicular lymphomas, B-cell lymphoma and Burkett's lymphoma; hematopoietic tumors of the myeloid family, including acute and chronic myeloid leukemia and promyelocytic leukemia; tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, neuroblastoma and glioma, as well as pre-cancerous lesions such as hereditary adenomatous polyposis;
• autoimmune or inflammatory diseases including but not limited to arthritis, such as rheumatoid arthritis, psoriasis, immune glomerulonephritis, inflammation of the intestine, transplant rejection and endotoxic shock , systemic lupus, Perythematosis, autoimmune diabetes mellitus, retinitis pigmentosa;
• cardiovascular diseases including but not limited to neurofibromatosis, atherosclerosis, pulmonary fibrosis, restenosis following angioplasty or vascular surgery, the formation of a hypertrophic scar, angiogenesis , venous graft disease, vasculopathy transplantation, ischemic lesions following myocardial infarction, lesions due to attack and reperfusion, cardiac arrhythmia; - neurodegenerative diseases, including but not limited to Alzheimer's disease, AIDS-related dementias, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, degeneration of the cerebellum; - viral and fungal infections including, but not limited to the herpes virus, smallpox, Eps tein-Barr, Sindbis and adenovirus, AIDS;
• degenerative diseases of the musculoskeletal system including, but not limited to osteoporosis and arthritis, aspirin-reactive rhinosinusitis, cystic fibrosis;
• - hematological diseases including, but not limited to chronic anemia, aplastic anemia and myeloplastic syndromes.
• the compounds of general formula (I) can be used to treat alopecia generated by chemotherapy, thrombocytopenia generated by chemotherapy, leukopenia or mucositis generated by chemotherapy.
• a subject of the invention is also medicaments which comprise a compound of general formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid or else a hydrate or a solvate of the compound of general formula (I).
• medicaments which comprise a compound of general formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid or else a hydrate or a solvate of the compound of general formula (I).
• the present invention relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the invention.
• These pharmaceutical compositions comprise an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and optionally one or more pharmaceutically acceptable excipients.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of general formula (I) above, or its salt, solvate or hydrate, if any, can be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules, chewing gum and oral solutions or suspensions, sublingual, buccal forms of administration, intratracheal, inraocular, intranasal, inhalation, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal or vaginal administration.
• the compounds according to the invention can be used in creams, ointments or lotions.
• a unit form of administration of a compound according to the invention in tablet form can comprise the following components:
• the dose of active principle can vary between 0.1 mg and 200 mg per kg of body weight and ⁇ per day. Although these dosages are examples of an average situation, there may be particular cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.
• Each unit dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg, of active ingredient in combination with one or more pharmaceutical excipients. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably from 0.5 to 2500 mg.
• the present invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of a compound according to the invention, of a pharmaceutically acceptable salt, of a solvate or of a hydrate of said compound.

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